Complex regulation of Gephyrin splicing is a determinant of inhibitory postsynaptic diversity.

Autor: Dos Reis R; INM, Université Montpellier, CNRS, INSERM, Montpellier, France., Kornobis E; Biomics, C2RT, Institut Pasteur, Paris, France.; Hub Bioinformatique et Biostatistique, Département de Biologie Computationnelle - USR 3756 CNRS, Institut Pasteur, Paris, France., Pereira A; INM, Université Montpellier, CNRS, INSERM, Montpellier, France., Tores F; BIP-D Plateforme de Bioinformatique Paris-Descartes, Institut Imagine, Paris, France., Carrasco J; UMR 3738, Unité de Régulation Épigénétique, Institut Pasteur, Paris, France.; Max Planck Institute of Immunobiology and epigenetics, Freiburg, Germany., Gautier C; Institut Imagine, INSERM - U1163, Unité mécanismes cellulaires et moléculaires des désordres hématologiques et implications thérapeutiques, Paris, France., Jahannault-Talignani C; INM, Université Montpellier, CNRS, INSERM, Montpellier, France., Nitschké P; BIP-D Plateforme de Bioinformatique Paris-Descartes, Institut Imagine, Paris, France., Muchardt C; UMR 3738, Unité de Régulation Épigénétique, Institut Pasteur, Paris, France., Schlosser A; Institute of Structural Biology, Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Str. 2, 97080, Würzburg, Germany., Maric HM; University of Würzburg, Biotechnology and Biophysics, Rudolf Virchow Zentrum Gebäude D15, Josef-Schneider-Straße 2, 97080, Würzburg, Germany., Ango F; INM, Université Montpellier, CNRS, INSERM, Montpellier, France. fabrice.ango@inserm.fr., Allemand E; UMR 3738, Unité de Régulation Épigénétique, Institut Pasteur, Paris, France. eric.allemand@inserm.fr.; Institut Imagine, INSERM - U1163, Unité mécanismes cellulaires et moléculaires des désordres hématologiques et implications thérapeutiques, Paris, France. eric.allemand@inserm.fr.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Jun 18; Vol. 13 (1), pp. 3507. Date of Electronic Publication: 2022 Jun 18.
DOI: 10.1038/s41467-022-31264-w
Abstrakt: Gephyrin (GPHN) regulates the clustering of postsynaptic components at inhibitory synapses and is involved in pathophysiology of neuropsychiatric disorders. Here, we uncover an extensive diversity of GPHN transcripts that are tightly controlled by splicing during mouse and human brain development. Proteomic analysis reveals at least a hundred isoforms of GPHN incorporated at inhibitory Glycine and gamma-aminobutyric acid A receptors containing synapses. They exhibit different localization and postsynaptic clustering properties, and altering the expression level of one isoform is sufficient to affect the number, size, and density of inhibitory synapses in cerebellar Purkinje cells. Furthermore, we discovered that splicing defects reported in neuropsychiatric disorders are carried by multiple alternative GPHN transcripts, demonstrating the need for a thorough analysis of the GPHN transcriptome in patients. Overall, we show that alternative splicing of GPHN is an important genetic variation to consider in neurological diseases and a determinant of the diversity of postsynaptic inhibitory synapses.
(© 2022. The Author(s).)
Databáze: MEDLINE
Externí odkaz: